Gram-negative germs (e.g. cholera germs, salmonella germs, colon bacillus) have compounds known as lipopolysaccharides (abbreviated as LPS) on the outer cell membrane, and it was thought that such compounds induced endotoxin shock.
It was known that LPS have various bioactivities including fetal toxicity; this is why it is so named an endotoxin. For example, LPS have a pyrogenetic action, a hemorrhage action, can induce encephalomyelitis, arthritis, and have a blastogenic action (macrophage activating action, B cell mitogenic activity, producing action of non-specific antibody, enhancing activity of cellular immunity etc.) and anti-tumor action (INF (interferon) inducing action, TNF (tumor necrosis factor) inducing action etc.).
Especially, LPS is effective as a non-specific immunity agent, and has an action inducing hemorrhage necrosis of tumor cells specifically by its TNF inducing activity, and therefore can be useful as an anti-tumor agent.
LPS is also useful for its inducing activity of IL-1 (interleukin-1) or interferon, not only enhancing its activity of cellular immunity but also stimulating of NK (natural killer) activity.
On the other hand, LPS is constituted from three kinds of materials, i.e. acidic protein, macromolecular polysaccharides and phospholipid, and the phospholipid but has been found as its active site by Westphal, Ludertz et al. ##STR2##
The phospholipid shown above is called lipid A, and it was known that lipid A alone possesses various activities like LPS.
The absolute structure of lipid A was unknown for many years, but recent studies have made clear that its structure is a disaccharideamine combined with fatty acids and phosphoric acids as shown below. See Nippon Saikin-gaku Zasshi 40(1), 57 (1985) and Proc. Natl. Acad. Sci. U.S.A., 80, 4624 (1983): ##STR3##
As a result of these recent studies, it has been discovered that each subunit above possesses activities like lipid A. In particularly, the reducing subunit was isolated as a biosynthesis precursor and was named lipid X. See Biol. Chem., 256, 10690 (1981) and Proc. Natl. Acad. Sci., 80, 4624 (1983).
Futher, a compound combined with a hexadecanoyl group on the hydroxy group of the .beta.-hydroxytetradecanoyl group on the 2nd position of lipid X as ester is named lipid Y.
Patent applications have been filed on the above lipid A, lipid X and lipid Y by Wisconsin Alumni Research Foundation. See WO-8404526 or EP-143840.
Non-reducing subunits were not found to be naturally occuring, and some of them were synthesized chemically, i.e. compounds of general formula: ##STR4## Examples are: Compound 1:
R.sup.1 = ##STR5## R.sup.2 =--H Compound 2: PA1 R.sup.1 =--CO--C.sub.13 H.sub.27 PA1 R.sup.2 =--PO(OH).sub.2 PA1 R.sup.A 1= ##STR6## R.sup.2 =--PO(OH).sub.2 See Agric. Biol. Chem., 48(1), 251 (1984) and FEBS LETT., 167, 226 (1984). PA1 R.sup.1 represents a single bond or an oxycarbonylalkylene group of from 2 to 20 carbon atoms; PA1 R.sup.2 and R.sup.6, independently, represent a hydrogen atom or a general formula: ##STR9## (wherein R.sup.10 represents a hydrogen atom, an alkyl or alkoxy group of from 1 to 7 carbon atom(s) or a halogen atom, and s represents 1, 2 or 3), respectively; PA1 R.sup.3 represents an alkylene group of from 1 to 20 carbon atom(s); PA1 R.sup.4 represents a hydrogen atom or a general formula: ##STR10## (wherein R.sup.11 represents a hydrogen atom, an alkyl or alkoxy group of from 1 to 7 carbon atom(s) or a halogen atom, and t represents 1, 2 or 3); PA1 R.sup.5 repesents an oxycarbonylalkylene group of from 2 to 20 carbon atoms; and R.sup.7 represents a hydrogen atom or a hydroxy group; PA1 W.sup.2 represents a group represented by A, B, D or E: PA1 A represents a general formula: ##STR12## B represents a general formula: ##STR13## D represents a general formula: ##STR14## and E represents a general formula: ##STR15## (in each of A, B, D and E, l and q each represents an integer of 11.about.15, m and m' each represents an integer of 6.about.12, n represents an integer of 6.about.10, l' and n' each represents an integer of 9.about.13, PA1 G represents a single bond or an alkylene group of from 1 to 4 carbon atom(s), PA1 Y.sup.2 represents a hydrogen atom, an alkyl or alkoxy group of from 1 to 7 carbon atom(s) or a halogen atom); PA1 W.sup.3 represents a group represented by L, M or Q: PA1 L represents a general formula: ##STR16## M represents a general formula: ##STR17## and Q represents a general formula: ##STR18## (in each of L, M and Q, Z represents a single bond or an alkylene group of from 1 to 4 carbon atom(s), p and p' each represents an integer of 6.about.12, q' represents an integer of 11.about.15, r represents an integer of 6.about.10, PA1 Y.sup.3 represents a hydrogen atom, an alkyl or alkoxy group of from 1 to 7 carbon atom(s) or a halogen atom); PA1 W.sup.4 represents a hydrogen atom, hydroxymethyl group or sulfoxymethyl group; PA1 with the proviso that when W.sup.4 represents hydroxymethyl group, (A,M), (A,Q), (D,M), (D,Q), and (E,M) as the combination of (W.sup.2, W.sup.3) are excluded, and when W.sup.4 represents sulfoxymethyl group, (A,M) and (E,M) as the combination of (W.sup.2, W.sup.3) are excluded;
Patent applications relating to the above compounds have been published. See Japanese Patent Publication No. 61-126093 and 61-126094.
Further, compounds replacing the hydroxy group on the 1st position with a hydrogen atom has benn described, i.e. compounds of general formula: ##STR7## wherein A represents O or NH, R.sup.2' represents C.sub.14 or C.sub.14 -O-C.sub.14, R.sup.3' and R4' represent a hydrogen atom or P, C.sub.14 represents a tetradecanoyl group, C.sub.14 -O-C.sub.14 represents a (3-tetradecanoyl)-tetradecanoyl group, and P represents a phosphoryl group, respectively. Stereo configuration of AR.sup.2' on the 3rd position is .alpha.-configuration or .beta.-configuration. See Japanese Patent Publication No. 61-172867.